Controlled drug release formulations offer several advantages over conventional dosage forms. They can provide more stable systemic drug concentrations, eliminating periods of toxic or sub-therapeutic levels. Release rates can be set by the polymer structure of the polymeric release formulation, its geometry and its interactions with drugs. Less effect from environmental variations is found from patient to patient. Bioavailability usually is increased because the drug in the polymer is protected from degradation by the body's clearance mechanisms. Furthermore, problems related to poor patient compliance are reduced because the patient does not have to take the drug as often.
Numerous investigations have been carried out on drug release from both hydrophobic and non-degradable polymers containing uniformly distributed drug. Silicone rubber (the common name for crosslinked polydimethylsiloxane) is one of the more commonly studied materials because acute tissue inflammation to filler-free silicone implants is very mild. For example, silicone has been used for release of steroids, hydrophobic drugs which easily permeate through silicone. (see Y. W. Chien, ACS Symposium Series, 33, 53-71 (1976).) Steroid release rates in humans were constant up to 18 days. This phenomenon was attributed to rapid permeation of the steroids through the matrix compared to diffusion of drug through a boundary layer at the surface. As the equilibrium concentration of a compound in silicone was increased relative to the equilibrium concentration of the aqueous solution, the in vitro release rate approached zero-order. (See T. J. Roseman, et al., ACS Symposium Series, 33, 33-52 (1976).
Other hydrophobic polymers that have been used for drug release include polyethylene and polethylene-vinyl acetate (polyEVA). Polyethylene films have been used for release of progesterone in rabbits. (see S. Yolles, Polymers in Medicine and Surgery, R. L. Kronenthal, et al., eds., (Plenum Press, New York 1975), 245-261.) In this case, release rates declined rapidly during the first 14 days, the maintained a steady level to 39 days. The copolymer polyEVA has been used to release a variety of proteins. In these polymers, interconnecting pores were created by the initially solid drug particles dispersed in the matrix. Drug release occurred when water diffused into the pores and dissolved the proteins and the protein then diffused through the water phase to the surface. (see R. Langer, Chem. Eng. Commun., 6, 1-48 (1980).)
Hydrophilic polymers also have been studied as drug releasing materials. Polyhydroxyethylmethacrylate (polyHEMA) is the most popular material for studying drug release because of its ease of synthesis and its biocompatibility which has been demonstrated through its widespread use as soft contact lenses. Partition and diffusion coefficients of inorganic salts add hydrophilic non-electrolytes in loosely (1%) crosslinked gels have been measured. (see S. Wisniewski, et al., J. Membr. Sci., 6, 299-308 (1980).) These compounds partitioned mainly in the bulk water of the gel therefore implying that diffusion occurred in the bulk water phase. PolyHEMA gels have also been used for release of hydrophobic compounds. (see J. M. Anderson. et al., ACS Symposium Series, 31, 167-179 (1976).)
Other hydrophilic polymers that have been used for drug release include polyethylene oxide (PEO)-polyurethane, polyvinyl alcohol((PVA), polyacrylamide, and a multi-polymeric system of methacrylate, ethacrylate and N-vinylpyrrolidone. (see M. P. Embrey, et al., Brit. Med. J., 28, 901-902, (1980); C. T. Reinhart, et al., J. Membr. Sci., 18, 227-239 (1984); B. K. Davis, Proc. Natl. Acad. Sci., U.S.A., 71, 3120-3123, (1974); S. Hosaka, et al., J. Appl. Polym. Sci., 23, 2089-2098, (1979). For example, PEO-polyurethane was used for nearly constant release of prostaglandin E.sub.2 for 10 hours. In the multipolymeric system, the composition of the polymer was varied to obtain networks of varying swelling ratios. Continuous release of erythromycin from these networks for four days was obtained.
Preparation of crosslinked materials by the reaction of polypropylene glycol (PPG) with polyglycidoxypropylmethylsiloxane (PGPMS) was described by Pekala et al. (J. Colloid & Interface Sci. 101, 1984, 120-8; Biomaterials, 7, 1986, 372-8). These crosslinked materials were synthesized for studying the blood compatibility of these materials.
Despite these previous findings, a need still exists for a material having a balance of hydrophobic and hydropilic properties suitable for continuous pharmaceutical delivery.